Trans-4-piperidine acetic acids and esters and racemic cis-4-piperidine acetic acids and esters

ABSTRACT

The preparation of quinine, quinidine, isomers and derivatives thereof from the correspondingly substituted 4-methylquinoline and 1-acyl(or 1-H)-3-vinyl(or lower alkyl)-4-piperidine acetic acid esters (or acetaldehyde) through alternative series of reaction steps which comprise, condensation, halogenation, deacylation, reduction, cyclization and hydroxylation, is described. Also described is the preparation of 1-acyl(or 1-H)-3vinyl-4-piperidineacetic acids and esters thereof and 1-acyl-3vinyl-4-piperidineacetaldehyde utilizing the corresponding 7acyldecahydro-2H-pyrido(3,4-d)azepin-2-one, prepared from 2-acyl1,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone. The end products are useful as antimalarial and antiarrhythmic agents.

United States Patent [191 Gutzwiller et al.

[4 1 Apr. 1, 1975 [75] Inventors: Juerg Albert Walter Gutzwiller,

Bettingen, Switzerland; Milan Radoje Uskokovic, Upper Montclair, NJ.

[73] Assignee: Hoffman-La Roche, Inc., Nutley,

[22] Filed: Aug. 1, 1973 [21] Appl. No.: 384,524

Related US. Application Data [60] Division of Ser. No. 212,774, Dec. 27,1971, Pat. No. 3,772,302, which is a continuation-in-part of Ser. No.104,784, June 27, 1969, abandoned, which is a continuation-in-part ofSer. No. 741,914, July 2, 1968, abandoned.

[52] US. Cl. 260/293.77, 260/293.76 [51] Int. Cl C07d 29/24 [58] Fieldof Search..... 260/293.77, 293.88, 293.76,

[56] References Cited OTHER PUBLICATIONS Rubtsov, Zhur. Obshchei Khim30:1498-1507 (1960).

Suszko et al., C.A. 61:10727g (1964). Lifshits et al., C.A. 40:3761(1946).

Woodward et al., JACS 67:860-874 (1945).

Primary Examiner-Henry R. .liles Assistant E.raminerS. D. WintersAttorney, Agent, or Firm-Samuel L. Welt; Bernard S. Leon; William G.Isgro [5 7] ABSTRACT The preparation of quinine, quinidine, isomers andderivatives thereof from the correspondingly substituted4-methylquinoline and 1-acyl(or l-l-l)-3-vinyl(or loweralkyl)-4-piperidine acetic acid esters (or acetaldehyde) throughalternative series of reaction steps which comprise, condensation,halogenation, deacylation, reduction, cyclization and hydroxylation, isdescribed. Also described is the preparation of l-acyl(orl-l-l)-3-vinyl-4-piperidineacetic acids and esters thereof andl-acyl-3-vinyl-4-piperidineacetaldehyde utilizing the corresponding7-acyldecahydro-2H- pyrido[3,4-d]azepin-2-one, prepared from2-acyll,3,4,7,8,8a-hexahydro-6(2l-l)-isoquinolone. The end products areuseful as antimalarial and antiarrhythmic agents.

9 Claims, No Drawings TRANS-4-PIPERIDINE ACETIC ACIDS AND ESTERS ANDRACEM IC C IS-4-PIPERIDINE ACETIC ACIDS AND ESTERS This is a division ofapplication Ser. No. 212,774 filed Dec. 27, 1971, now U.S. Pat. No.3,772,302, issued Nov. 13, 1973, which in turn is acontinuation-.in-part of Ser. No. 104,784, filed Jan. 7, 1971, nowabandoned, which is a continuation-in-part of Ser. No. 837,354, filedJune 27, 1969, now abandoned, which is a continuation-in-part of Ser.No. 741,914, filed July 2, 1968, now abandoned.

BRIEF SUMMARY OF THE INVENTION The invention relates to a process forpreparing quinine, quinidine, isomers and derivatives thereof whichcomprises:

a. condensing the correspondingly substituted 4- methyl-quinoline withracemic or optically active cis or trans l-acyl (or l-l-l)-3-vinyl(orlower alkyl)-4- piperidineacetic acid ester to yield the correspondingracemic or optically active cis or trans 4-{3-[ l-acyl(orl-H)-3-vinyl(or lower alkyl)-4-piperidyl]-2-oxopropyl}quinoline;

b. deacylating, if necessary, and reducing the product of step (a) toyield the corresponding racemic or optically active epimeric 4-{cis ortrans-3-[3-vinyl(or lower alkyl)-4-piperidyl]-2-hydroxypropyl}quinolines. If desired, this reaction product can beacylated to yield racemic or optically active epimeric 4-{cis ortrans-3-[3- vinyl(or lower alkyl)-4-piperidyl]-2Q-acyloxypropyl}quinolines or dehydrated to yield racemic or optically active cis ortrans 4-{cis or trans 3-[3-vinyl(or lower a1kyl)-4-piperidyl]prop-l-enyl}quinolines;

c. an alternate process comprises condensing the correspondinglysubstituted 4-methylquinoline with racemic or optically active cis ortrans l-acyl-3-vinyl(or lower alkyl)-4-piperidine-acetaldehyde to yieldthe corresponding racemic or optically active epimeric 4- {cis ortrans-3-[ l-acyl-3-vinyl(or lower alkyl)-4-piperidyl]-2g-hydroxypropyl}quinolines, and deacylating this reactionproduct to yield the corresponding racemic or optically active epimeric4-{cis or trans-3-[3- vinyl (or loweralkyl)-4-piperidyl]-2-hydroxypropyl quinolines;

d. cyclizing the hydroxy, acyloxy or prop-l-enyl quinoline product ofstep (b) or (c) to yield the corresponding racemic or optically active4-{a-[5-vinyl(or lower alkyl)-2-quinuclidinyl]-methyl}quinoline,epimeric in positions 2 and 5;

e. hydroxylating the product of step (d) to yield the correspondingracemic or optically active a-[5-vinyl(or loweralkyl)-2-quinuclidinyll-4-quinolinemethanol, epimeric in positions 01, 2and 5; and

f. recovering the desired reaction product.

An alternate process comprises:

g. halogenating the product of step (a) above to yield the correspondingracemic or optically active epimeric 4- {cis or trans 3-[l-acyl-3-vinyl(or lower alkyl)-4-piperidyl]-1lI-halo-Z-oxopropyl}quinolines;

h. reducing the product of step (g) with subsequent cyclization to yielda mixture of the corresponding racemic or optically active epimeric4-{cis or trans-3-[ lacyl-3-vinyl( or lower alkyl )-4-piperidyl]-l Q24oxapropyl} quinolines;

i. deacylating the product of step (g) to yield a mixture of thecorresponding racemic or optically active epimeric 4-{cis or trans3-[3vinyl(or lower alkyl)-4- piperidyl]- l 5,2L-oxapropyl} quinolines;

j. cyclizing the product of step (h) to yield the corresponding racemicor optically active a-[5-vinyl(or loweralkyl)-2-quinuclidinyl]-4-quinolinemethanol, epimeric in positions a, 2and 5; and

k. recovering the desired reaction product.

The end products are useful as antimalarial and antiarrhythmic agents.

In another aspect, the invention relates to a process for preparingracemic or optically active cis or trans 1- acyl(orl-l-I)-3-vinyl-4-piperidineacetic acid and esters thereof and racemic oroptically active cis or trans .1- acyl-3-viny1-4-piperidine-acetaldehydeby:

a. nitrosating a racemic or optically active cis or trans7-acyl-decahydro-ZH-pyrido[3,4-d]azepin-2-one to yield the correspondingracemic or optically active cis or trans 7-acyll-nitroso-decahydro-2l-l-pyrido[ 3 ,4- d]azepin-2-one;

b. pyrrolyzing the reaction product of step (a) to yield thecorresponding racemic or optically active cis or transl-acyl-3-vinyl-4-piperidineacetic acid; and

c. hydrolyzing, if desired, and esterifying the reaction product of step(b) to yield the corresponding racemic or optically active cis or transl-acyl(or l-l-l)-3-vinyl -4-piperidineacetic acid ester; and

d. reducing and acylating the reaction product of step (c) to yieldracemic or optically active cis or translacyl-3-vinyl-4-piperidineacetaidehyde.

in a further aspect, the invention relates to an alternate process forpreparing racemic or optically active cis and trans l-acyl(orl-H)-3-vinyl-4-piperidineacetic acid and esters thereof by:

a. alcoholizing a racemic or optically active cis or trans7-acyl-decahydro-ZH-pyrido[3,4-d]azepin-2-one to yield the correspondingracemic or optically active cis or transl-acyl-3-(Z-aminoethyl)-4-piperidineacetic acid esters;

b. methylating the reaction product of step (a) to yield thecorresponding racemic or optically active cis or transl-acyl-3-(2-dimethylaminoethyl)-4- piperidineacetic acid esters;

c. oxidizing the reaction product of step (b) to yield the correspondingracemic or optically active cis or trans1-acyl-3-(2-dimethylaminoethyl)-4- piperidineacetic acid ester N-oxide;and

d. pyrolyzing the reaction product of step (c) to yield the desiredacetic acid and esters thereof.

In still another aspect, the invention relates to a process forpreparing racemic or optically active cis or trans7-acyl-decahydro-2H-pyrido[3,4-d]azepin-2-one which comprises:

a. hydrogenating a racemic or optically active2-acyll,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone to yield thecorresponding racemic or optically active cis or trans2-acyl-octahydro-6(2H)-isoquinolone; and

b. converting the reaction product of step (a), through a SchmidtRearrangement, to the corresponding racemic or optically active cis ortrans 7-acyldecahydro-2H-pyrido[ 3 ,4-d lazepin-Z-one.

Alternatively, by a process which comprises:

a. converting through a Schmidt Rearrangement, a racemic or opticallyactive 2-acyl-l ,3,4,7,8,8a-hexahydro-6(2l-l)-isoquinolone to thecorresponding racemic or optically active2-acyl-l,2,3,4,7,8,9,9a-octahydro- 6H-pyrido[3,4-d]azepin-6-one; and

b. hydrogenating the reaction product of step (a) to yield thecorresponding racemic or optically active cis or trans7-acyl-decahydro-2H-pyrido[3,4-d]azepin- 2-one.

In yet another aspect, the invention relates to novel compounds.

DETAILED DESCRIPTION OF THE INVENTION The term lower alkyl as usedherein denotes a hydrocarbon group containing l-7 carbon atoms, such asmethyl, ethyl, propyl, butyl and the like; methyl and ethyl arepreferred. .The term lower alkoxy denotes a lower alkyl ether group inwhich the lower alkyl moiety is described as above, such as methoxy,ethoxy, propoxy, butoxy and the like; methoxy and ethoxy are preferred.The term halogen denotes all of the halogens, i.e., bromine, chlorine,fluorine and iodine. Preferred are chlorine and bromine. The term acyl"denotes lower alkanoyl of 1-7 carbon atoms such as formyl, acetyl,propanoyl, butanoyl, heptanoyl, and the like; ar-lower alkanoyl,preferably phenyl-lower alkanoyl wherein phenyl may be substituted byone or more lower alkyl, lower alkoxy or halogen groups such as benzoyland the like. The term aryl means phenyl which may be substituted by oneor more lower alkyl, lower alkoxy or halogen groups. The term aralkylmeans a hydrocarbon group of 7-12 carbon atoms such as benzyl,phenethyl, phenylpropyl and the like. The term acyloxy means an acyloxywherein the acyl moiety is as hereinbefore described, for example, loweralkanoyloxy and ar-lower alkanoyloxy.

The process for preparing quinine, quinidine, isomers and derivativesthereof is exemplified by Reaction Scheme la, la, la, lb, lb, lb".

Scheme Ia IIa ( om J wherein m is O, l or 2; R is hydrogen, hydroxy,halogen, trifluoromethyl, lower alkyl, lower alkoxy, or when m is 2, Rtaken together with an adjacent R is also methylenedioxy; R is vinyl orlower alkyl, preferably ethyl; R is hydrogen or lower alkyl; is hydrogenor acyl, and R is lower alkyl, aryl or ar-lower alkyl. As is evidentfrom the above when m is 2, R or the like is individually selected fromthe various groupings hereinbefore described.

Compounds of the formula Ia and [la above are useful as antimalarial andantiarrhythmic agents.

In Reaction Scheme la, 4-methyl-quinolines of formula X, which are knowncompounds or are analogs of known compounds readily obtained by knownprocedures, are condensed with l-acyl (or l-H)-3(R)- vinyl(or loweralkyl)-4(S)-piperidineacetic acid ester of formula lXa, antipode or itsracemate which are known compounds, are analogs of known compoundsreadily obtained by known procedures, or are prepared as hereinafterdescribed, in the presence of a base, for

example, sodium hydride, an alkali metal alkoxide such as sodiummethoxide, or lithium dialkylamide such as lithium diisopropylamide toyield 4-{3-[ l-acyl(or l-H 3(R)-vinyl(or lower alkyl)-4(S)-piperidyl]-2-oxopropyl}quinoline of formula Villa, antipode or its racemate. Thecondensation is suitably carried out at room temperature; however,temperatures above or below room temperature may be employed.Preferably, the condensation is conducted at a temperature within therange of about and about 50C. Moreover, the condensation can be suitablycarried out in the presence of an inert organic solvent, for example, ahydrocarbon, such as benzene, hexane and the like, or an ether such asether, tetrahydrofuran or dioxane, or dimethylformamide orhexamethylphosphoramide.

The 4-{3-[l-acyl(or ll-l)-3(R)-vinyl(or lower alkyl)-4(S)-piperidyl]-2-oxopropyl} quinoline ture of epimeric4-{3-[3(R)-vinyl(or lower alkyl)-4(S)- piperidyl]-2-hydroxypropyl}quinolines of formula Vla, their antipodes or racemates by simultaneousdeacylation, if necessary, and reduction. The deacyla-.

hydrochloric or sulfuric acid as the deacylating agent.- lf desired, thecompound of formula Vla can be esterified to the corresponding mixtureof epimeric 4-{3- of formula Villa, antipode or its racemate isconverted to the mixypropyl}quinolines of formula Vlla, their antipodesor racemates utilizing known procedures, for example, reaction with thecorresponding organic acid in the presence of a catalyst, such as borontrifluoride. Alternatively, if desired, the compound of formula Vla canbe converted to cis and trans 4-{3-[3(R)-vinyl(or loweralkyl)-4(R)-piperidyl]-prop-l-enyl} quinolines of formula Va, theirantipodes or racemates utilizing a dehydrating agent such as thionylchloride, phosphorus oxychloride, phosphorus pentachloride and the like,in the presence of an organic base, for example, a tertiary amine suchas pyridine, triethylamine and the like, at a temperature within therange of about 0 to about room temperature.

The cyclization of epimeric 4-{3-[3(R)-vinyl(or loweralkyl)-4(S)-piperidyl]-2-hydroxy(or acyloxy)- propyl}qu inolines offormulas Vla and Vlla, their antipodes or racemates, respectively andcis and trans 4- 3-[3(R)-vinyl(or loweralkyl)-4(R)-piperidyl]-propl-enyl} quinolines of formula Va, theirantipodes or racemates to 4-{a[5(R)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(S) and 2(R)-yl]-methyl} quinolines of formulas llla andNa, their antipodes or its racemate is carried out utilizing a cyclizingagent, for example, an organic acid, such as glacial acetic acid or thelike. The cyclization is suitably carried out at room temperature;however, temperatures above or below room temperature may also beemployed. It is preferred to employ a temperature within the range ofabout 25 to about C. Moreover, the cyclization can be convenientlyconducted in the presence of an inert organic solvent, for example, ahydrocarbon such as benzene or toluene, or an ether, such as diethylether or tetrahydrofuran.

The hydroxylation of the compounds of formulas Illa and lVa or theirracemates to a(R)-[5(R)-vinyl(or loweralkyl)-4(S)-quinuclidin-2(S)-yl]-4- quinolinemethanol ofv formula Ia,its antipode or racemate and a(S)-[5(R)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol of formula lIa, its antipode orracemate, respectively, is carried out, for example, in the presence ofmolecular oxygen 7 and a reducing agent, such as dimethylsulfoxide,pyridine, triphenylphosphine, platinum black, or a trialkylphosphite,such as triethylphosphite, or the like, in a strongly basic solution. I

A suitable base for the reaction described above CI' Ia 1) in l 'l'Scheme Ia CHO E f l R XXIIIa wherein R R and m are as previouslydescribed and R, is acyl.

In Reaction Scheme Ia an alternative process for the preparation ofcompounds of formula VIa is described. 4-Methylquinolines of formula Xare condensed with l-acyl-3(R)-vinyl-(or -lower alky)-4(S)-piperidineacetaldehyde of formula XXllla, its antipode or racemate whichare new compounds and are prepared as hereinafter described, in thepresence of base, for example, sodium hydride, and alkali metal alkoxidesuch as sodium methoxide, or lithium dialkylamide such as lithiumdiisopropylamide to yield the mixture of epimeric4-{3-[l-acyl-3(R)-vinyl-(or lower alkyl)-4(S)-piperidyll-2c-hydroxypropyl} quinolines of formula XXlVa, theirantipodes or racemates. The compounds of formula XXlVa are deacylated tothe corresponding mixture ofepimeric 4-{3-3(R)-vinyl(or loweralkyl)-4(S)-piperidyl]-2-hydroxypropyl} quinolines of formula VIa, theirantipodes or racemates, utilizing a deacylating agent, for example,alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide,a reductive deacylating agent such as lithium aluminum hydride, sodiumaluminum hydride, diisobutyl aluminum hydride and the like. Preferably,the deacylation is suitably carried out at room temperature; however,temperatures above and below room temperature may be employed. Moreover,the deacylation can be suitably carried out in the presence of an inertorganic solvent for example, a lower alkanol, such as methanol orethanol, or an ether, such as tetrahydrofuran or dioxane.

wherein R R R., and m are as previously described and X is halogen.

In Reaction Scheme Ia, an alternative process for the conversion ofcompounds of formula Vllla' to the compounds of formulas la and Ila isdescribed. The conversion of the 4-{3-[ l-acyl-3-(R)-vinyl(or loweralkyl)-4(S)-piperidyl]-2-oxopropyl}quinoline of formula Vllla, itsantipode or racemate to the corresponding mixture of epimeric 4-{3-[l-acyl-3(R)-vinyl(or lower alkyl)-4(S )-piperidyl]-l-halo-2-oxopropyl}quinolines of formula XXa, their antipodes orracemates, respectively, is effected utilizing a halogenating agent suchas N-bromo-succinimide, N-chloro-succinimide, N- bromoacetamide and thelike. The halogenation can be conducted in an inert organic solvent, forexample, a hydrocarbon such as benzene, toluene and the like, ahalogenated hydrocarbon such as carbon tetrachloride; an ether such asdiethylether, tetrahydrofuran, dioxane and the like. Conveniently, thereaction can be initiated by a free radical catalyst such asdibenzoylperoxide or' by irradiation with infrared. The temperature isnot critical, however, it is preferred to conduct the reaction at atemperature in the range of about room temperature and the refluxtemperature of the reaction mixture.

The conversion of the epimeric compounds of formula XXa, their antipodesor racemates to the corresponding mixture-of diastereomeric4-{3-[1-acyl-3(R)- vinyl(or lower alkyl)-4(S)-piperidyl]- l 2;,2g-oxapropyl} quinolines of the formula XXIa, their antipodes orracemates can be effected utilizing a reducing agent, for example,alkali metal hydrides such as sodium borohydride, potassium borohydride,lithium tritertiarybutoxyaluminum hydride and the like. The reduction isconveniently effected in an inert organic solvent, for example,aliphatic alcohols such as methanol, ethanol and the like; ethers suchas diethylether, tetrahydrofuran, dioxane and the like, at a temperaturein the range of about 70C. and about the reflux temperature of thereaction mixture.

The conversion of the compound of formula XXIa to the correspondingmixture of the diastereomeric 4-{3- [3(R)-vinyl(or loweralkyl)-alkyl-4(S)-piperidyl]- l(,ZQ-oxopropylquinolines of the formulaXXlIa, their antipodes or racemates is effected using a deacylatingagent, for example, alkali hydroxides such as sodium hydroxide,potassium hydroxide, or a reducing deacylating agent, for example,dialkylaluminum hydride such as diisobutylaluminum hydride, or an alkalimetal aluminum hydride such as lithium aluminum hydride, sodium aluminumhydride and the like. The deacylation is conveniently conducted in thepresence of an I I NRl will a inert organic solvent, for example, loweralkanols such as methanol, ethanol and the like, hydrocarbons such astoluene and the like, others such as diethylether, tetrahydrofuran andthe like. The deacylation temperature is not critical. Conveniently, itmay be in the range of about 70C. to about the reflux temperature of thereaction mixture.

The conversion of the compounds of formula XXlla to the correspondingmixture comprising oz(R)-[5 (R)- vinyl(or loweralkyl)-4(S)-quinuclidin-2(S)-yl]-4- quinolinemethanol of formula Ia, itsantipode or racemate and oz(S)-[5(R)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol of formula Ila, its antipode orracemate is effected by reaction with a weak organic or inorganicprotonic acid, for example, water, ammonium chloride, lower alkanolssuch as methanol, ethanol and the like, Lewis acids such as aluminumoxide, aluminum chloride, boron trifluoride and the like. Conveniently,conversion is conducted in the presence of an inert organic solvent, forexample, carbon disulfide, hydrocarbons such as benzene, toluene and thelike, chlorinated hydrocarbons such as dichloromethane,carbontetrachloride, chloroform and the like, and others such asdiethylether, tetrahydrofuran, dioxane and the like. The temperature ofthe reaction is not critical. Conveniently, it may be in the range ofabout 0C. and about the reflux temperature of the reaction mixture.

Scheme Ib COOR;

IXb VIIIb H R2 H R2 H NH M H H z I 1L 0 OH R0 E R3 (R1)? (R1)m VIb V111)R2 R2 I (Tin (gs (R1)m i I (R1) 1% N N IIIb IVb om (R9111 J N N whereinR,, R ,R R R and m are as previously de- Scheme -H)-3(S)-vinyl(or loweralkyl)-4(S )-piperidineacetic scribed.

The hereinafter described reaction steps of Reaction Scheme lb areeffected utilizing the procedures and conditions set forth in Scheme la.The 4-methylquinoline of formula X is condensed with 1-acyl(or 1- acidester of formula lXb, its antipode or racemate to yield 4-{3-[l-acyl(orlH)-3(S)-vinyl(or lower alkyl)- 4(S)-piperidyl]-2-oxopropyl quinoline offormula VIIlb, its antipode or racemate. The compound of for- X mulaVIIlb is deacylated, if necessary, and reduced to 4 the mixture ofepimeric 4-{3-[3(S)-vinyl(or lower alky- N/l)-4(S)-piperidyl]-2-hydroxypropyl}quinolines of for- XXIVb mula Vlb,their antipodes or racemates. If desired, the

compounds of formula VIb can be esterified to the mixture of epimeric4-{3-[3(S)-vinyl(or lower alkyl)-4(S)- piperidyl]-2-acyloxypropyl}quinolines of formula Vllb, their antipodes or racemates or,alternatively, it R2 H can be converted tocis and trans4-{3-[3(S)-vinyl(or lower alkyl)-4(R)-piperidyl]-prop-l-enyl}quinolinesof j formula Vb, their antipodes or racemates. The com pounds of formulaVb, VIb or Vllb are cyclized to 4- 1 /i\ {a-[5(S)-vinyl(or loweralkyl)-4(S)-quinuclidin-2(S) and 2(R)-yl-] methyl}quinolines of formulaslllb and lVb, their antipodes or racemates. The compounds of 0H formulaslIIb and Nb are hydroxylated to a(R) -[5(S)- vinyl(or loweralkyl)-4(S)-quinuclidin-2(S)-yl]-4- quinolinemethanol of formula lb, itsantipode or racemate and 01(8) -[5(S)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol of formula N llc, its antipodeor racemate, respectively. VIb

The hereinafter described reaction steps of Reaction Scheme Ib areeffected utilizing the procedures and G 4;; conditions set forth inScheme Ia 4-Methyl- 5 H quinolines of formula X are condensed withl-acyI- 3(S)-v inyl(or lower alkyl)-4(S)- piperidineacetaldehyde offormula XXlIlb, its antipode (Rom (B1) J or racemate which are newcompounds and are pre- N N pared as hereinafter described, to yield themixture of 10 IlIa,b-IVa, b Ia, b-IIa, b P y y (f lower Y can also beeffected utilizing molecular oxygen and a )-P P l"' yp py h of formulacatalyst such as platinum, tris(triphenylphosphine)r- XXWb, antipodes orracemates- The COmPOUPdS hodium chloride or the like or by oxidationutilizing a ofiformula xxlvbflfe deacylated the Correspondmg 15 compoundsuch as selenium dioxide, ruthenium tetrox- P y lower ide, palladiumacetate, mercuric acetate, thallium tri- )-P P Y yp py qumolmes ofacetate, manganese dioxide, cerium (IV) oxide, or the mula VIb, theirantipodes or racemates. |ike Alternate procedures for the conversion ofthe com- The hydroxylation of the compound of Formulas "la, 20 pounds ofFormula Vla,b to the corresponding comb-lVa, b to the end products ofFormulas Ia, b-lla, b, pound of formula lIla,b-IVa,b are exemplified inReaci.e., ti0n Scheme V.

R H R H )1 2 2 \/\I|\I-H KT 06H! OH OH om J l)m J N N VIa,b XXXI R H R Hi N-H N CaHzi o soc@ecm XXXIII (Ron:

XXXII 1119., b-IVa, b

The conversion of compounds Vla,b to the corresponding compounds offormula XXXI is effected utilizing a chloroformate such asbenzylchloroformate. The compounds of formula XXXI are converted to thecompounds of formula XXXlI by tosylation with a compound such asp-toluenesulfonylchloride or p-toluenesulfonic acid anhydride in asolvent such as pyridine. The conversion of the compounds of formulaXXXII to the corresponding compound of formula XXXIII is effected by theremoval of the N- carbobenzoxy group utilizing, for example, aceticacid/hydrogen bromide mixture. The cyclization of the compounds offormula XXXIII to the corresponding compound of formula llIa,b-lVa,b iseffected by heating in an organic solvent such as methanol, ethanol,dimethylformamide, dimethylsulfoxide'and the like.

Scheme Ib" wherein R R R',, m and X are as previously described.

In Reaction Scheme lb", an alternative process for the conversion ofcompounds of formula VIIIb' to the compounds of formulas Ib and Ilb isdescribed. The

conversion of the 4- 3- l-acyl-3(S)-vinyl(or loweralkyl)-4-(S)-piperidyl]-2-oxopropyl }quinoline of formula Vlllb, itsantipode or racemate to the corresponding mixture of. epimeric4{3-[l-acyl-3(S)-vinyl(or lower alkyl )-4( S )-piperidyl]- lfi-halo-Z-oxopropyl}quinolines of formula XXb, their antipodes orracemates. respectively, is effected utilizing a halogenating agent suchas N-bromo-succinimide, N-chloro-succinimide, N- bromoacetamide and thelike. The halogenation can be conducted in an inert organic solvent, forexample, a hydrocarbon such as benzene, toluene and the like, ahalogenated hydrocarbon such as carbon tetrachloride; an ether such asdiethylether, tetrahydrofuran, dioxane and the like. Conveniently, thereaction can be initiated by a free radical catalyst such asdibenzoylperoxide or by irradiation with infrared. The temperature isnot critical, however, it is preferred to conduct the reaction at atemperature in the range of about room temperature and the refluxtemperature of the reaction mixture.

The conversion of the epimeric compounds of formula XXb, their antipodesor racemates to the corresponding mixture of diastereomeric 4- 3-[l-acyl-3(S)- vinyl(or lower alkyl)-4(S)-piperidyl] -l,2toxapropyl}quinolines of the formula XXIb, their antipodes or racematescan be effected utilizing a reducing agent, for example, alkali metalhydrides such as sodium borohydride, potassium borohydride, lithiumtritertiarybutoxyaluminum hydride and the like. The reduction isconveniently effected in an inert organic solvent, for example,aliphatic alcohols such as methanol, ethanol and the like; ethers suchas diethylether, tetrahydrofuran, dioxane and the like, at a temperaturein the range of about 70C. and about the reflux temperature of thereaction mixture.

The conversion of the compound of formula XXIb to the correspondingmixture of the diastereomeric 4-{3- [3(S)-vinyl(or lower-alkyl)-4(S)-piperidyl]-lQ24 oxapropyl}quinolines of the formula XXllb,their antipodes or racemates is effected using a deacylating agent, forexample, alkali hydroxides such as sodium hydroxide, potassiumhydroxide, or a reducing deacylating agent, for example, dialkylaluminumhydride such as diisobutylaluminum hydride, or an alkali metal aluminumhydride such as lithium aluminum hydride, sodium aluminum hydride andthe like. The deacylation is conveniently conducted in the presence ofan inert organic solvent, for example, lower alkanols such as methanol,ethanol and the like, hydrocarbons such as toluene and the like, etherssuch as diethylether, tetrahydrofuran and the like. The deacylationtemperature is not critical. Conveniently, it may be in the range ofabout 70C. to about the reflux temperature of the reaction mixture.

The conversion of the compounds of formula XXllb to the correspondingmixture comprising a(R)-[5(S)- vinyl(or loweralkyl)-4(S)-quinuclidin-2(S)-yl]-4- quinolinemethanol of formula lb, itsantipode or racemate and a(S)-[5(S)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(R)-yll-4-quinolinemethanol of formulalIb, its antipode orracemate is effected by reaction with a weak organic or inorganicprotonic acid, for example, water, ammonium chloride, lower alkanolssuch as methanol, ethanol and the like, Lewis acids such as aluminumoxide, aluminum chloride, boron trifluoride and the like. Conveniently,conversion is conducted in the presence of an inert organic solvent, forexample, carbon disulfide, hydrocarbons such as benzene, toluene and thelike, chlorinated hydrocarbons such as dichloromethane,carbontetrachloride, chloroform and the like, and ethers such asdiethylether, tetraliydrofuran, dioxane and the like. The temperature ofthe reaction is' not critical. Conveniently, it may be in the range ofabout C. and about the reflux temperature of the reaction mixture.

The various other process aspects of the invention are exemplified bythe following reaction schemes Ila,

llb, Illa, lllb and IV.

wherein R and R are as previously described, and R is lower alkyl, arylor ar-lower alkyl.

In Reaction Scheme Ila, the conversion of7-acyldecahydro-2l-l-pyrido[3(R),4(S)-d]axepin-2-one of formula Xla, itsantipode or racemate to 7 acyl-1-nitroso-decahydro-Zl-I-pyrido[3(R),4(S)-d]-azepin- 2-one of formulaXlla, its antipode or racemate, respectively, is carried out utilizing anitroseting agent, such as for example, sodium nitrite or dinitrogentetroxide. Conveniently, the reaction can be conducted in the presenceof a solvent, for example, an organic acid such as acetic acid, or achlorinated hydrocarbon such as carbon tetrachloride. The nitrozation isconveniently conducted at a temperature within the range of about 0C. toabout room temperature, preferably at 0C.

The compound of formula Xlla is converted tolacyl-3(R)-vinyl-4(S)-piperidineacetic acid of formula Xllla, itsantipode or racemate, respectively, by pyrolysis. Conveniently, thepyrolysis is conducted at a temperature within the range of about roomtemperature to about 200C, preferably at a temperature within the rangeof about 100C. to about 130C. Conveniently, a high boiling solvent suchas xylene, decaline and the like, can be utilized in the reaction.

' The compound of formula Xllla is converted to lacyl(orl-l-I)-3(R)-viny1-4(S)-piperidineacetic acid ester of formula IXc, itsantipode or racemate, respectively, utilizing an esterifying agent, forexample, a lower alkanol, such as methanol, ethanol, propanol and thelike, in the presence, of, for example, an inorganic acid such ashydrochloric acid sulfuric acid and the like. When R is hydrogen,however, the esterification is preceded by hydrolysis in the presenceof, for example, an aqueous inorganic acid, such as hydrochloric acid,sulfuric acid and the like.

Compounds of formula Xla, wherein R is alkyl, for instance, ethyl, canbe prepared as described in Scheme IV.

XIIIb wherein R R and R are as previously described.

In a like manner, in Reaction Scheme Ilb, the conversion of7-acyl-decahydro-2l-I-pyrido[3(S),4(S)- d]azepinZ-one of Formula Xlb,its antipode or racemate to 7-acyll -nitroso-decahydro-2 H-pyrido[3(S),4(S)-d]azepin-2-one of Formula Xllb, its antipode orracemate, respectively, is carried out. The compound of Formula Xllb isconverted to l-acyl- 3(S)-vinyl-4(S)-piperidineacetic acid of FormulaXlllb, its antipode or racemate, respectively, by pyrolysis. Thecompound of Formula XllIb is converted to lacyl(orlH)-3(S)-vinyl-4(S)-piperidineacetic acid IXd 5 ester of Formula lXd,its antipode or racemate, respectively.

Scheme IIIa COOR; COORa wherein R R and R are as previously described.

In Reaction Scheme Illa, 7-acyl-decahydro-2H- pyrido[3(R),4(S)-d]azepin-2-one of formula XIa, its antipode or racemate isconverted to l-acyl-3(R)-(2- aminoethyl)-4(S)-piperidineacetic acidester of formula XIVa, its antipode or racemate, respectively, utilizingan alcoholizing agent, for example, a lower alkanol such as methanol,ethanol, propanol and the like, in the presence of, for example,anhydrous inorganic acid such as hydrochloric acid, sulfuric acid andthe like. Conveniently, the alcoholysis is conducted at a temperaturewithin the range of about room temperature to about the boiling point ofthe alkanol.

The compound of formula XIVa is converted to 1-acyl-3(R)-(2-dimethylaminoethyl)-4(S)- piperidineacetic acid ester offormula XVa, its antipode or racemate, respectively, utilizing amethylating agent such as, for example, formic acid/formaldehyde mixtureor formaldehyde/Raney nickel. The N- methylation is convenientlyconducted at a temperature within the range of about room temperature toabout the boiling point of the methylating agent.

The compound of formula XVa is converted tolacyl-3(R)-(2-dimethylaminoethyl)-4(S)- piperidineacetic acid esterN-oxide of formula XVIa, its antipode or racemate, respectively,utilizing an oxidizing agent, for example, hydrogen peroxide or aperorganic acid such as, peracetic acid. The oxidation is convenientlyconducted in the presence of a solvent, for example, lower alkanol, suchas methanol, ethanol, propanol and the like, or a hydrocarbon such asben- .zene and the like. The oxidation is conveniently conducted at atemperature within the range of about 0 to about room temperature,preferably at 0C.

The compound of formula XVla is converted to lacyl(orl-H)-3(R)-vinyl-4(S)-piperidineacetic acid ester of formula lXc,-itsantipode or racemate, respectively, by pyrolysis. Such pyrolysis isconveniently conducted at a temperature in the range of about 80 toabout 200C, preferably at a temperature within the range of about 90 toabout 125C. When R, is hydrogen, however, the pyrolysis is followed byhydrolysis and reesterification.

m Scheme HIb XIVb wherein R R, and R are previously described.

In a like manner, in Reaction Scheme IIIb,7-acyldecahydro-2H-Pyrido[3(S),4(S)-d]azepin-2-one of Formula Xlb, itsantipode or racemate is converted tol-acyl-3(S)-(Z-aminoethyl)-4(S)-piperidineacetic acid ester of FormulaXIVb, its antipode or racemate, respectively. The compound of FormulaXIVb is converted to l-acyl-3(S)-(Z-dimethylaminoethyl)-4(S)-piperidineacetic acid ester N-oxide of Formula XVIb, its antipode orracemate, respectively. The compound of Formula XVlb is converted tol-acyl-3(S)-(2-. dimethylaminoethyl)-4(S)-piperidineacetic acid esterN-oxide of Formula XVIb, its antipode or racemate, respectively. Thecompound of Formula XVlb is converted to l-acyl(or l-H)-3(S)-vinyl-4(S)-piperidineacetic acid ester of Formula lXd, its antipode or racemate.

Scheme IV wherein R is as previously described.

In the Reaction Scheme IV, racemic 2-acyll,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone offormula XVII is converted to the racemic cis and trans2-acyloctahydro-6(2I-I)-isoquinolones of formula XVIIIa and XVlIIb,respectively, utilizing a hydrogenating agent, for example, hydrogen inthe presence of palladium or rhodium catalyst. Conveniently, thehydrogenation can be conducted in the presence ofa solvent, for example,a lower alkanol such as methanol, ethanol, propanol and the like, withor without an inorganic acid such as hydrohalic acid, for example,hydrochloric acid and the like. The hydrogenation can be convenientlyconducted at a temperature within the range of about room temperatureand about 50C.

The racemates of the compounds of formula XVIIIa or XVIIIb are resolvedto the corresponding optical antipodes by conventional methods which arefurther illustrated by Examples 3, 4,5.

The conversion of 2-acyl-4a(S),8a(R)-octahydro- 6(2H)-isoquinolone offormula XVIIIa, its antipode or racemate to7-acyldecahydro-2H-pyrido[3(R),4(S)- dlazepin-Z-one of formula XIa, itsantipode or racemate, respectively, is carried out utilizing the knownSchmidt rearrangement, i.e., the reaction of the compound of formulaXVIIIa with sodium azide in the presence of an inorganic acid such assulfuric acid or polyphosphoric acid, with or without solvent, at atemperature within the range of from about to about 150C.

In a like manner, 2-acyl-4a(S),8a(S)-octahydro- 6(2l-I)-isoquinolone ofFormula XVIIIb, its antipode or racemate is converted to7-acyl-decahydro-2H- pyrido[3(S),4(S)-d]azepin-2-one of Formula XIb, itsantipode or racemate, respectively.

The racemic compound of Formula XVII is converted to the racemic2-acyl-l,2,3,4,7,8,9,9aoctahydro-6I-I-pyrido[3,4-d1azepin-6-one ofFormula XIX utilizing the Schmidt rearrangement as hereinbeforedescribed. The compound of Formula XIX is converted to the racemiccompound of Formula XIa utilizing a hydrogenating agent such as hydrogenin the presence of a catalyst, such as rhodium or palladium, in asolvent, for example, an alkanol, such as ethanol, methianol and thelike, in the presence of an inorganic acid, such as hydrochloric acid.

and IVe wherein n is O to 2; R is vinyl or lower alkyl; R is hydrogen,hydroxy, lower alkyl, lower alkoxy, trifluoromethyl, halogen, or when nis 2, R taken together with an adjacent R is also methylenedioxy; when Ris hydrogen, R is C -C alkoxy, lower alkyl, trifluoromethyl or halogen;when R is other than hydrogen and n is l. R; is lower alkoxy, loweralkyl, hydroxy, hydrogen, trifluoromethyl, halogen, or taken togetherwith an adjacent R is methylenedioxy; and when R is other than hydrogenand n is 2, R hydrogen, and their antipodes and racemates.

Also included in the purview of the invention are compounds of theformulas CHSO CHaO Ind and

wherein R is methyl or C -C lower alkyl, their antipodes and racemates.

4() Compounds of formulas lIIc, IIId, IVc and IVd are usefulintermediates.

In still another aspect, the invention relates to compounds of theformulas 5 wherein n is 0 to 2; R 15 vinyl or lower alkyl; R ishydrogen, hydroxy, lower alkyl,,lower alkoxy, trifluoromethyl, halogen,or when n is 2, R taken together with an adjacent R is alsomethylenedioxy; when R, is hydrogen, R is C -C alkoxy, lower alkyl,trifluoromethyl or halogen; when R is other than hydrogen and n is l, R,is lower alkoxy, lower alkyl, hydrogen, trifluoromethyl, halogen, ortaken together with an adjacent R is methylenedioxy; and when R is otherthan hydrogen and n is 2, R is hydrogen and their antipodes andracemates.

As is evident from the above R or R or the like are individuallyselected from the various groupings hereinbefore described. Moreover,when m or n is 2, R or referred R or the like can additionally form withan adjacent wherein R is methyl or C -C lower alkyl, their antipodes andracemates. Compounds of formulas Ille, IIlf, We and IVf are usefulintermediates.

In a further aspect, the invention relates to compounds of the formulaswherein n is to 2; R is vinyl or lower alkyl; R is hydrogen, hydroxy,lower alkyl, lower alkoxy, trifluoromethyl or halogen, and when n is 2,R taken together with an adjacent R is also methylenedioxy; when R ishydrogen, R is C -C alkoxy, lower alkyl, trifluoromethyl or halogen;when R is other than hydrogen and n is 1, R is lower alkoxy, loweralkyl, hydrogen, trifluoromethyl or halogen, or taken together with anadjacent R is methylenedioxy; and when R is other than hydrogen and n is2, R is hydrogen, and their antipodes and racemates, andpharmaceutically acceptable acid addition salts.

Exemplary of the.compounds of formulas lo and [1c are:

6,8-dimethoxy-a(R)-[(S)-ethyl-4(S)-quinuclidin-2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 6,8-dimethoxy-3-epi-dihydrocinchonidine]its' antipode and racemic analog;

7-chloro-a(R)-[5(S)-ethyl-4(S)-quinuclidin-2(S)- yl]-4-quinolinemethanol[hereinafter referred to as 7- chloro-3-epidihydrocinchonidine]itsantipode and racemic analog;

6,7-methylenedioxy-a(R)-[5(S)-ethyl-4(S)-quinuclidin-2(S)-yl]-4-quinolinemethanol [hereinafter to as 6,7'-methylenedioxy-3-epidihydrocinchonidine] its antipode and racemicanalog;

7-trifluoromethyl-a(R)-[5(S)-ethyl-4(S)-quinuclidin-2(S)-yll-4-quinolinemethanol [hereinafter referred to as7-trifluoromethyl-3-epidihydrocinchonidine] its antipode and racemicanalog;

6,8-dimethoxy-a(S)-[5(S)-ethyl-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol [hereinafter referred to as6,8-dimethoxy-3-epi-dihydrocinchonine] its antipode and racemic analog;

7-chloro-a(S)-[5(S)-ethyl-4(S)-quinuclidin-2(R)- yl]-4-quinolinemethanol[hereinafter referred to as 7- chloro-3-epi-dihydrocinchonine] itsantipode and racemic analog;

6,7-methylenedioxy-a(S)-[5(S)-ethyl-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol [hereinafter referred to as6',7-methylenedioxy-3-epidihydrocinchonine] its antipode and racemicanalog;

7-trifluoromethyl-a(S)-[5(S)-ethyl-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol [hereinafter referred to as7-trifluoromethyl-3-epidihydrocinchonine] its. antipode and racemicanalog.

Also included in the purview of the invention are compounds of theformulas Ell CH O- 01130 \N/ \NJ IId and

wherein R is vinyl, methyl or C -C alkyl, their antipodes and racematesand pharmaceutically acceptable acid addition salts.

Also included in the purview of the invention are compounds of theformula:

The antipode of 6-methoxy-a(R)'-[5(S)-ethyl-4(S)-quinuclidin-2(S)-yl]-4-quinolinemethanol [hereinafter referred to as6'-methoxy-3-epi-dihydrocinchonidine or 3-epi-dihydroquinine] and itsracemic analog (Compound A) and The antipode of6-methoxy-a(S)-[5(S)-ethyl-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol [hereinafter referred to as6-methoxy-3-epi-dihydrocinchonine or 3-epi-dihydroquinidine] and itsracemic analog (Compound B). The compounds of formulas 10, Id, IIc andIId, as well? as Compounds A and B, are useful also as antimalarial andantiarrhythmic agents. 7

The compounds of the formula IXa have demonstrated cardiovascularactivity, such as, hypotensive activity. The pharmacologically usefulcardiovascular activity is demonstrated in warm-blooded animalsutilizing standard procedures. For example, the test compound isadministered to anesthetized (30 mg/kg sodium pentobarbital),artificially respired (Palmer Pump) dogs. Femoral arterial bloodpressure and respiratory resistance (measured in terms of pressure) are'recorded on a direct writing oscillographic recorder. A

series ofcontrol responses of the blood pressure and d-monotartrate isutilized as the test substance at a dose of 4 mg/kg. intravenously, thefollowing results are obtained:

blood pressure 25 for 35 minutes serotonin N E.

Central Vagus Stimulation slight inhibition Carotid Occlusion blockingHypertension N.E. Norepinephrine slight inhibition Histamine slightinhibition The compounds of Formula IXa also exhibit antiestrogenicactivity. This useful estrogenic activity is demonstrated inwarm-blooded animals. For example, the test compound is administeredonce daily for three consecutive days to groups of ten immature femalerats (40-50 grams). On the first treatment day, all rats are injectedsubcutaneously with 0.25 meg. estradiol in sesame oil. On the fourthday, uteri are removed at autopsy and weighed on a torsion balance.

When meroquinene-t-butylester d-monotartrate is utilized as the testsubstance at a dosage of 1 mg/kg. p.o., an 1 1 percent antiestrogeninhibition is observed with a l2 percent uterine change.

The compounds offormulas Ia, Ila, lb and Ilb, including compounds of theformulas Ic, Id, llc and 11d, as well as compounds A and B, and theirpharmaceutically acceptable acid addition salts possess antimalarial andantiarrhythmic properties and are therefore useful as antimalarial andantiarrhythmic agents. Their pharmacologically useful antiarrhythmicactivity is demonstrated in warm-blooded animals utilizing standardprocedures, for example, the test compound is administered to preparedmongrel dogs. The chest cavity of the experimental animal previouslyanesthetized using a combination of sodium barbitol, 300 mg/kg. andpentobarbitol, 15 mg/kg, i.e., is opened up through the third rightinterspace under artificial respiration and the pericardium is cut andsutured to the wall of the thorax so as to maintain the heart in apericardial cradle throughout the course of the test procedure. Arterialpressure is monitored by inserting a polyethylene cannula into the aortavia the left carotid artery and is measured with an appropriate Stathampressure transducer. During the course of the experiment, electricalactivity of the heart is viewed both on an oscilloscope and recorded ona Sanborn polyviso using standard ECG lead II. The heart is alsoobserved visually. The antiarrhythmic assay of the test drug isundertaken using a modification of the method of Scherf and Chick, 1951.A dripping of 1 percent solution of acetylcholine is applied to thesinus node and the atrium is irritated by pinching with a pair offorceps. This procedure produces a continuous artiral arrhythmia whichmostly consists of atrial fibrillation. Since hypokalemia produces asusceptibility to atrial fibrillation (Leveque, 1964), 2 units/kg. ofinsulin is administered 30 minutes before the start of the acetylcholinedrip. Once atrial fibrillation is established, there is a 10 minutewaiting period before the test drug is administered. The test drugs areadministered at the rate of l mg/kg/minute until normal sinus rhythmappears or until 30 mg/kg. of drug is administered.

When 6-methoxy-0z(R)-[5(R)-ethyl-4(S)- quinuclidin-2(S)-yl-4-quinolinemethanol is utilized as thetest substance at a dosage of about 4.0rug/leg, an antifibrillatory effect is observed for more than 60minutes.

Their pharmacological useful antimalarial activity is demonstrated inwarm-blooded animals using standard procedures, for example, the testsubstance is administered to albino mice in variable amounts. Albinomice are inoculated with about 5-10 million red cells infected with P.Bergei. Treatment is started on the first day after inoculation, and thedrug is administered per os during 4 consecutive days. On the seventhday of infection, smears are made, stained with giemsa andmicroscopically examined for P. Bergei.

When racemic 7'-methoxy-dihydrocinchonidine dihydrochloride or racemic7-methoxydihydrocinchonine dihydrochloride is utilized as the testsubstance at dosages in the range of mg/kg. to about 250 mg/kg., themicroscopical examination of the blood smears is free of P. Berghei(negative). When 6'-methoxy-a(R) [5(R)-ethyl-4(S)-quinuelidin-2(S)-yl]-4-quinolinemethanol [dihydroquinine] or 6-methoxy-a(R)-[5(R)-ethyl-4(S)-quinuclidin-2(S)-yl]- 4-quinolinemethanolis utilized as the test substance at a dose of about 200 mg/kg., themicroscopical examination of the blood smears is free of P. Berghei(negative). The compounds of formulas la, Ila, lb and IIb, including thecompounds of formulas lc, Id, llc and Ild, as well as compounds A and B,and their pharmaceutically acceptable acid addition salts have effectsqualitatively similar, for example, to those of quinine and quinidine,known for their therapeutic uses and properties. Thus, the compounds ofthe invention demonstrate a pattern of activity associated withantimalarials and antiarrhythmics of known efficacy and safety.

Furthermore, the compounds of the formulas Ia, Ila, lb and Ilb,including the compounds of formulas lc, Id, I10 and 11d, as well ascompounds A and B, can be utilized as flavoring agents in beverages inthe same manner as quinine is now used for this purpose.

The compounds of formulas Ia, Ila, lb and IIb, including the compoundsof formulas lc, ld, llc and lld, as well as compounds A and B, form acidaddition salts and such salts are also within the scope of thisinvention. Thus, the compounds of formulas la, Ila, Ib and llb,including the compounds of formulas lc, Id, llc and Ild, as well ascompounds A and B, form pharmaceutically acceptable addition salts with,for example, both pharmaceutically acceptable addition salts with, forexample, both pharmaceutically acceptable organic and inorganic acids,such as acetic acid, succinic acid, formic acid, methanesulfonic acid,p-toluenesulfonic acid, hydrochloric acid, nitric acid, phosphoric acid,sulfuric acid, and the like.

The products of the invention can be incorporated ple, they are usefulfor oral or parenteral application -with the usual pharmaceuticaladjuvant materials, e.g.,

organic or inorganic inert carrier materials such as water, gelatin,lactose, starch, magnesium stearate, talc, vegetable oils, gums,polyalkyleneglycols, and the like. The pharmaceutical preparations canbe employed in a solid form, e.g., as tablets, troches, suppositories,capsules, or in liquid form, e.g., as solutions, suspensions oremulsions. The pharmaceutical adjuvant material can includepreservatives, stabilizers, wetting or emulsifying agents, salts tochange the osmotic pressure or to act as buffers. They can also containother therapeutically active materials.

The quantity of active medicament which is present in any of theabove-described dosage forms is variable. The frequency with which anysuch dosage form will be administered will vary, depending upon thequantity of active medicament present therein, and the needs andrequirements of the pharmacological situation.

Due to the possible different spatial arrangements of their atoms, it isto be understood that the compounds of this invention may be obtained inmore than one possible stereoisomeric form. The novel compounds, asdescribed and claimed, are intended to embrace all such isomeric forms.Accordingly, the examples included herein are to be understood asillustrative of particular mixtures of isomers or single isomers and notEXAMPLE 1 Preparation of racemic cis 2-benzoyl-octahydro-6-2H)-isoquinolone from racemic2-benzoyl-l,3,4,7,8,8ahexahydro-6(2H)-isoquinolone To a solutioncontaining 151 g. of racemic2-benzoyll,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone in 3,000 ml. ofabsolute ethanol were added 300 ml. of 3N aqueous hydrochloric acid and30 g. of 5% rhodium of alumina catalyst. The mixture was hydrogenated atroom temperature and atmospheric pressure until the uptake of hydrogenceased. The catalyst was removed by filtration and washed thoroughlywith ethanol. The filtrate was partially evaporated in vacuo, dilutedwith 3,500 ml. of dichloromethane and washed with 3N aqueoushydrochloric acid, saturated aqueous sodium bicarbonate and sodiumchloride solutions. The organic phase was dried over anhydrous sodiumsulfate and evaporated to dryness to yield a crystalline product. Gaschromatographic analysis indicated that it contained 61.9% of racemiccis 2-benzoy1-octahydro-6(2H)- isoquinolone and 13% of racemic trans2-benzoyloctahydro-6(2H)-isoquinolone. The product was recrystallizedtwice from benzene to give racemic cis 2-benzoyloctahydro-6(2H)-isoquinolone having a melting point of 147-148.5.

EXAMPLE 2 Preparation of racemic trans 2-benzoyl-octahydro-6(2H)-isoquinolone from racemic 2-benzoyl-1,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone To a solution containing 25.5g. of racemic 2- benzoyl- 1 ,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone in1,000 ml. of 95% ethanol were added 2.5 g. of 10% palladium on carboncatalyst and the mixture was hydrogenated at room temperature and 3atmospheres pressure until the uptake of hydrogen ceased. The catalystwas removed by filtration and washed with 95%ethano] anddichloromethane. The filtrate was evaporated to dryness to yield an oilwhich crystallized on trituration with ether. The product wasrecrystallized twice from absolute ethanol to yield racemic transZ-benzoyloctahydro-6(2H)-isoquinolone, which after two additionalrecrystallizations from absolute ethanol, had a melting point ofl57.5-159.

EXAMPLE 3 To a solution containing 23.4 g. of rac. trans-2-benzoyloctahydro-6( lH)-isoquinolone in 2 l. of anhydrous benzene wasadded 2.24 g. of p-toluenesulfonic acid and 9.83 g. of(-)-butane-2(R),3(R)-diol. The resulting solution was refluxed for 3hours and the water which formed was collected in a water separator.After the addition of 18 ml. of pyridine, the mixture was diluted to4 1. with benzene, washed four times with ml. of water, dried overanhydrous sodium sulfate and evaporated to dryness in vacuo. The lasttraces of pyridine were removed by codistillation with toluene in vacuo.The crystalline residue, 29.62 g., was fractionally crystallized byrepeating several times the following system:

Preparation of 29.62 g. mixture of ketals 6 hours reflux with distilledpetroleum ether (b.p. 30-60 C.)

I! insoluble part soluble part recrystallization recrystallization fromether from ethanol-water 1:1

(5'H)-isoquinoline], 12.45

EXAMPLE 4 a(S)-2-benzoyloctahydro-6(2H)-isoquinolone, having a meltingpoint of 151-l53 (from absolute ethanol); [04],, 61.8 (c 1.01, CHC14a(S),8a(S)-2-benzoyloctahydroof 2-benzoylv EXAMPLE 5 Preparation of4a(R),8a(R)-2-benzoyloctahydro- 6(2l-l)-isoquinolone A solutioncontaining 0.329 g. of 2-benzoyl-4(R),5(R)-dimethyl-1',2,3,4,4a(R),7',8',8a(R)- octahydrospiro[l,3-dioxolane-2,6 5 'H )-isoquinoline] in 50 ml. of 70% acetic acid washeated at 100-105 for 4 hours and 40 minutes. The reaction mixture wasevaporated in vacuo diluted with 500 ml. of benzene, washed with 50 ml.of 2N aqueous sodium carbonate and 3 times with 50 m1. of water, driedover anhydrous sodium sulfate and evaporated in vacuo to yield 0.256 g.of 4a(R),8a(R)-2-benzoyloctahydro-6(2H)- isoquinolone having a meltingpoint of l5ll53 (from absolute ethanol); [th, 62.60 (c 1.005, CHC1EXAMPLE 6 Preparation of racemic cis7-benzoyl-decahydro-2l-lpyrido[3,4-d]-azepin-2-one from racemic cis 2-benzoyl-octahydro-6( 2H )-isoquinolone To a suspensioncontaining 20.6 g.of finely ground racemic cis 2-benzoyl-octahydro-6(2H)-isoquinolone in800 g. of polyphosphoric acid were added 10.0 g. of sodium azide, andthe mixture was stirred 16 hours at 5560. After cooling at roomtemperature, the reaction mixture was poured onto crushed ice. Theresulting solution was made alkaline with solid sodium carbonate at 0,and was extracted thoroughly with dichloromethane. The organic phase waswashed with water, dried over anhydrous sodium sulfate and evaporated todryness in vacuo. The oily residue crystallized on trituration withacetone. Fractional crystallization of the crystalline product fromacetone yielded cis 7-benzoyldecahydro-2l-l-pyrido[3,4-d]azepin-2-one,which after one recrystallization from absolute ethanol and threerecrystallizations from acetone had a melting point of 167l68.5.

EXAMPLE 7 Preparation of racemic trans7-benzoyl-decahydro-2l-lpyrido[3,4-d]-azepin-2-one from racemic trans 2-benzoyl-octahydro-6(2H)-isoquino1one To a mixture containing 5.15 g. oftrans 2- benzoy1octahydro-6(2H)-isoquinolone and 200 g. ofpolyphosphoric acid were added 2.5 g. of sodium azide and the reactionmixture was stirred at 5560 for 16 hours. After cooling to roomtemperature, the polyphosphoric acid was hydrolyzed by addition of ice.The resulting solution was made alkaline with concentrated sodiumcarbonate solution and extracted thoroughly with dichloromethane. Theextract was washed with water, dried over anhydrous sodium sulfate andevaporated to dryness to yield 5.45 g. of crystalline racemic trans7-benzoyl-decahydro-ZH-pyrido[3,4-d]-azepin- 2-one. Afterrecrystallization from ethanol/ether it had a melting point of l87-l89.

EXAMPLE 8 Preparation of a(S),9a(S)-7-benzoy1decahydro-2H-pryrido[3,4,-d]azepin-2-one To a mixture of finely ground 2.57 g of4a(S),8a(S)- 2-benzoyloctahydro-6(2l-l)-isoquinolone and 100 g. ofpolyphosphoric acid was added 1.3 g. of sodium azide. The reactionmixture was stirred at 5560C. (bath) for 16 hours, cooled to roomtemperature and poured into ca. 380 g. of crushed ice. After the ice hadmelted, the resulting solution was made alkaline with 6N aqueous sodiumcarbonate (370 ml.) and extracted 3 times with 300 ml. of methylenechloride. Methylene chloride extract was washed 3 times with 40 ml. ofwater, dried over anhydrous sodium sulfate and evaporated to dryness. togive 2.72 g. of crystalline 5a(S),9a(S)-7- benzoyldecahydro-ZH-pyrido[ 3,4-d]azepin-2-one. From absolute ethanol it crystallized with one moleof ethanol, m.p. 200203C., [(11 37.83 (c. 1.0547, CHCl on drying losesethanol to give anhydrous form, m.p. 100.

EXAMPLE 9 Preparation of racemic 2-benzoyl-l,2,3,4,7,8,9,9aoctahydro-6l-l-pyrido[3,4-d]azepin-6-one from racemic2-benzoyll ,3,4,7,8,8a-hexahydro-6( 2H isoquinolone To a suspensioncontaining 1.02 g. of finely ground racemic 2-benzoyll,3,4,7,8,8a-hexahydro-6( 2H isoquinolone in 40 g. of polyphosphoric acidwas added 0.5 g. of sodium azide and the reaction mixture was stirred at120 for 30 minutes. After cooling to room temperature, ice was added.The resulting solution was made alkaline with saturated aqueous sodiumcarbonate at 0 and was extracted with dichloromethane. Thedichloromethane extract was washed with water, dried over anhydroussodium sulfate and evaporated to dryness. The product was crystallizedby trituration with acetone to give racemic2-benzoy1-1,2,3,4,7,8,9,9aoctahydro-6H-pyrido[3,4-d]azepin-6-one havinga melting point of 2l9-221.

EXAMPLE 10 Preparation of racemic cis 7-benzoyl-decahydro-2H-pyrido[3,4-d]-azepin-2-one from racemic 2-benzoyl-1,2,3,4,7,8,9,9a-octahydro-6l-l-pyrido[3,4-d]azepin- 6-one To a solutioncontaining 5.4 g. of racemic2-benzoyll,2,3,4,7,8,9,9a-octahydro-oH-pyrido[3,4-d]azepin- 6-one in 450ml. of absolute ethanol were added 10 ml. of 3N aqueous hydrochloricacid and 5.4 g. of 5% rhodium on alumina catalyst. The reaction mixturewas hydrogenated at room temperature and atmospheric pressure until theuptake of hydrogen ceased. Thereafter, the catalyst was removed byfiltration and washed thoroughly with ethanol. The filtrate wasneutralized with 2N aqueous sodium carbonate and evaporated to a smallvolume in vacuo. The residue was extracted with 1,000 ml. ofdichloromethane. The extract was washed with water, dried with anhydroussodium sulfate and evaporated to dryness. The non-crystalline productexhibited an lR-spectrum identical to that of the racemic cis7benzoyl-decahydro-ZH-pyrido[3,4-d]azepin- 2-one of Example 6, and afterbeing recrystallized twice from acetone, had a melting point of 162l65.

' EXAMPLE 1 1 Preparation of racemic cis l-benzoyl-3-(2-aminoethyl)-4-piperidineacetic acid ethyl ester from racemic cis7-benzoyl-decahydro-2l-l-pyrido[3,4- d]azepin-2-one A solutioncontaining 2.8 g. of racemic cis7-benzoyldecahydro-2H-pyrido[3,4-d]azepin-2-one in 500 ml. of 5%ethanolic hydrochloric acid was refluxed for hours. Thereafter, thesolvent was removed by evaporation in vacuo. The residue was taken up in1,200 ml.

of dichloromethane. The resulting solution was shaken with a solutioncontaining 0.53 g. of sodium carbonate in ml. of water, dried overanhydrous sodium sulfate and evaporated to yield oily racemic cis1benzoyl-3- (2-aminoethyl)-4-piperidineacetic acid ethyl ester.

EXAMPLE 12 Preparation of racemic trans l-benzoyl-3-(2- EXAMPLE 13Preparation of racemic cis l-benzoyl-3-vinyl-4- piperidineacetic acidethyl ester (racemic N- benzoylmeroquinene ethyl ester) from racemic cis1- benzoyl-3-( 2-aminoethyl)-4-piperidineacetic acid ethyl ester Amixture containing 1.91 g. of racemic cislbenzoyl-3-(2-aminoethyl)-4-piperidineacetic acid ethyl ester, 1.38 g.of formic acid and 1.05 g. of 37% formaldehyde was heated for 1 hour at100. After cooling to room temperature, 3.5 ml. of concentratedhydrochloric acid were added and the mixture thus obtained wasevaporated to dryness in vacuo. The residue was dissolved in 50 ml. ofwater. The solution was washed by shaking with ether, made alkaline toabout a pH 8 with 2N sodium carbonate and extracted thoroughly withdichloromethane. The extract was washed with water, dried over anhydroussodium sulfate and evaporated to dryness in vacuo to give oily racemiccis 1-benzoyl-3- (Z-dimethylaminoethyl)-4-piperidineacetic acid ethylester. To the stirred solution containing this product in 10 ml. ofmethanol were added 2 ml. of 30% aqueous hydrogen peroxide at 0. Thereaction mixture was warmed to room temperature and stirred for 16hours. The excess of hydrogen peroxide was decomposed by addition ofplatinum black with stirring for 1 hour at 0. The platinum black wasseparated by filtration and washed with methanol. The filtrate wasevaporated to dryness in vacuo to yield racemic cis l-benzoyl-3-(2-dimethylaminoethyl)-4-piperidineacetic acid ethyl ester N-oxide as anoil. Heating of this product in vacuo at a temperature from 90 to 125C.over a period of minutes yielded racemic N-benzoylmeroquinene ethylester, which. after purification by preparative thin layerchromatography and recrystallization from hexane, had a melting point of66-68.

ester from racemic trans l-benzoy1-3-(2-aminoethyl)- 4-piperidineaceticacid ethyl ester 1-benzoyl-3-(2- A mixture containing 1.4 g. of racemictrans 1- benzoyl-3-(2-aminoethyl)-4-piperidineacetic acid ethyl ester,1.4 g. of formic acid and 1.1 g. of 37% aqueous formaldehyde was heatedat 100. The reaction mixture became a clear solution and a vigorousevolution of gas occurred, which ceased after 1.5 hours. After coolingto room temperature, 1 ml. of concentrated hydrochloric acid was addedand the mixture was evaporated in vacuo. The residue was dissolved inml. of water, washed by shaking with ether, made alkaline with 2Naqueous sodium carbonate and extracted thoroughly with dichloromethane.The extract was dried over anhydrous sodium sulfate and evaporated toyield racemic trans l-benzoyl-3-(2- dimethylaminoethyl)-4-piperidineacetic acid ethyl ester.

EXAMPLE 15 Preparation of racemic trans l-benzoyl-3-(2-dimethylaminoethyl)-4-piperidineacetic acid ethyl ester N-oxide fromracemic trans 1-benzoyl-3-(2- dimethylaminoethyl)-4-piperidineaceticacid ethyl ester To a stirred solution containing 0.73 g. of racemictrans l-benzoyl-3-(2-dimethylaminoethyl)-4- piperidineacetic acid ethylester in 10 ml. of methanol was added 1 ml. of 30% hydrogen peroxide at0. The reation mixture was allowed to warm to room temperature and wasthen stirred overnight. The excess of hydrogen peroxide was decomposedby stirring with platinum black for 2 hours at 0C. The platinum blackwas removed by filtration and the filtrate'evaporated to drynessyielding racemic trans 1-benzoyl-3-(2-dimethylaminoethyl)-4-piperidineacetic acid ethyl ester N-oxide.

EXAMPLE 16 Preparation of racemic trans l-benzoyl-3-vinyl-4-piperidineacetic acid ethyl ester from racemic trans 1-benzoyl-3-(Z-dimethylaminoethyl)-4-piperidineacetic acid ethyl esterN-oxide A flask containing 0.63 g. of racemic trans l-benzoyl-3-(2-dimethylaminoethyl)-4-piperidineacetic acid ethyl ester N-oxide waspyrolyzed at 90-120 for 20 minutes. The product was chromatographed on a400 g. silica gel column with ether to yield racemic translbenzoyl-3-vinyl-4-piperidineacetic acid ethyl ester as a glass.

EXAMPLE 1? Preparation of racemic cis7-benzoyl-l-nitrosodecahydro-2H-pyrido[3,4-d]azepin-2-one from racemiccis, 7-benzoyl-decahydro-2H-pyrido[ 3,4-d]azepin- 2-one To a solutioncontaining 5.521 g. of nitrogen tetroxide in 360 ml. of carbontetrachloride at 70 were added 9.84 g. of anhydrous sodium acetate. Themixture was allowed to warm to 0 and a solution containing 10.88 g. ofracemic cis 7-benzoyl-decahydro-2l-lpyrido[3,4-d]azepin-2-one in 40 ml.of dichloromethane was added with stirring. After 30 minutes at 0, themixture was poured into a slurry of ice and water. The resulting mixturewas placed in a separatory funnel and the organic phase was separated.The aqueous phase was extracted thoroughly with ice-colddichloromethane. The combined organic phases were washed with water,dried over anhydrous sodium sulfate, and evaporated to dryness at C. invacuo to yield oily racemic cis7-benzoyl-l-nitroso-decahydro-ZH-pyridol3,4-d]- azepin-Z-one.

EXAMPLE 18 Preparation of racemic trans7-benzoyl-1-nitrosodecahydro-2l-l-pyrido[3,4-d]azepin-2-one from racemictrans 7-benzoyl-decahydro-2H-pyrido[3,4- d]azepin-2-one To 100 ml. ofcarbontetrachloride solution containing g. of nitrogentetroxide at 70were added 2.46 g. of anhydrous sodium acetate. The mixture was allowedto warm to 0, and 2.6 g. of racemic trans7-benzoyldecahydro-2H-pyrido[3,4-d]-azepin-2-one in 50 ml. ofdichloromethane were added with stirring. The reaction mixture wasmaintained at 0 for 30 minutes. Thereafter, it was poured into a slurryof ice and water, transferred to a separatory funnel and the organicphase was removed. The aqueous phase was extracted with three 250 ml.portions of dichloromethane. The organic phases were combined, washedwith water, dried over anhydrous sodium sulfate and evaporated todryness to yield trans 7-benzoyl-l-nitroso-decahydro- 2H-pyrido[3,4-d]azepin-2-one, a green yellow powder. All operations were carriedout at 0.

EXAMPLE 19 Preparation of racemic N-benzoyl-meroquinene [racemic cisl-benzoyl-3-vinyl-4-piperidineacetic acid] from racemic cis7-benzoyl-l-nitroso-decahydro-2H- pyridol3,4-d]azepin-2-one The racemiccis 7-benzoyl-l-nitroso-decahydro-ZH- pyrido[3,4-d]azepin-2-one fromExample 17 was placed in a flask fitted with a reflux condenser andheated under nitrogen on an oil bath maintained at 125 for about 1 hour.The residue was taken up in 50 ml. of 1N potassium hydroxide, dilutedwith 50 ml. of water and washed by shaking with ether. The aqueous phasewas neutralized with 50 ml. of 1N hydrochloric acid and extracted withether. The ether phase was washed with water, dried over anhydrousmagnesium sulfate and evaporated to dryness to yield racemic N-benzoyl-meroquinene, as an oil.

EXAMPLE 20 Preparation of racemic trans l-benzoy1-3-vinyl-4-piperidineacetic acid from racemic trans 7-benzoyl-1-nitroso-decahydro-2l-l-pyrido-[3,4-d]azepin-2-one The product of Example18, i.e., racemic trans 7- benzoyll -nitroso-decahydro-2l-l-pyrido[3,4-d]azepin- 2-one-was heated at 125 under nitrogen for 1 hour. Theproduct was taken up in 13 ml. of 1N aqueous potassium hydroxide and 30ml. of water, washed with four 100 ml. portions of ether, neutralizedwith 13 ml. of 1N aqueous hydrochloric acid and extracted with four 200'ml. portions of ether. The ethereal extract was washed with 70 ml. ofwater, which was combined with aqueous phase, dried over anhydrousmagnesium sulfate and evaporated to yield oily racemic translbenzoyl-3-vinyl-4-piperidineacetic acid.

EXAMPLE 21 Preparation of 1-benzoyl-3(S)-vinyl-4(S)- piperidineaceticacid To 143 ml. of 0.15M solution of dinitrogen tetroxide incarbontetrachloride immersed in a dry ice-acetone bath were added 3.51g. of anhydrous sodium acetate,

and the mixture was allowed to warm to 0C. A solution containing 3.86 g.of 5a(S),9a(S)-7-benzoyldecahydro- 2H-pyrido[3,4-d]azepin-2-one in 50ml. of methylene chloride was added with stirring, and after standingfor 30 minutes at 0C. the mixture was poured into a slurry of ice andwater (280ml.). The resulting mixture was placed in a separatory funneland the organic phase was removed. The aqueous phase was extracted 3times with 430 ml. of methylene chloride. The combined organic phaseswere washed with ml. of water, dried over anhydrous sodium sulfate andevaporated in vacuo. All these operations were carried out at 0C. Itgave quantitative yield of pale yellow powder, 1-nitroso-5a(S),9a(S)-7-benzoyldecahydro-2H- pyrido[3,4-d]azepin-2-one,which was processed immediately further.

The nitroso product was heated at C. (bath) under nitrogen. Initiallyviolent reaction ceased slowly after 30 minutes. The residue (3.92 g.)was taken up in 19 ml. of 1N aqueous potassium hydroxide, diluted withwater (60 ml.) and washed 4 times with ml. of ether. It was thenneutralized with 19 ml. of 1N aqueous hydrochloric acid and extracted 4times with 300 ml. of ether. The ethereal extract was washed with 60 ml.of water, dried over anhydrous magnesium sulfate and evaporated in vacuoto give 2.34 g. of oily lbenzoyl-3(S)-vinyl-4(S)-piperidineacetic acidwhich contained minor impurities (tlc).

EXAMPLE 22 Preparation of racemic N-benzoylmeroquinene methyl ester[racemic cis l-benzoyl-3-vinyl-4-piperidineacetic acid methyl ester]from racemic N- benzoylmeroquinene [racemic cis l-benzoyl-3-vinyl-4-piperidineacetic acid] To a stirred solution containing 5.29 g. ofracemic N- benzoylmeroquinene in 500 ml. of ether was added 1 g. ofdiazomethane in 50 ml. of ether. Stirring was continued for 15 minutes.The excess diazomethane was decomposed by a dropwise addition of glacialacetic acid until the yellow color disappeared. The reaction mixture wasdiluted to 1,000 ml. with ether, washed with 2N sodium carbonate andwater, dried over anhydrous magnesium sulfate and evaporated in vacuo toyield oily N-benzoylmeroquinene methyl ester.

EXAMPLE 23 Preparation of l-benzoyl-3(R)-vinyl-4(S)-piperidineacetaldehyde from l-benzoyl-3(R)-vinyl- 4(S)-piperidineaceticacid methyl ester To a dry ice cooled solution of 1.48 g. (0.005 mole)of l-benzoyl-3(R)-vinyl-4(S)-piperidineacetic acid methyl ester in 100ml. of toluene was added dropwise (5 min.) with stirring 8 ml. (ca.0.012 mole) of a 25% solution of diisobutyl aluminum hydride in toluene.Stirring was continued for 30 min. at 78, then 5 ml. of methanol-water(1:1) was added, and stirring at --78 was continued. After 90 min., 0.6ml. (0.005 mole) of benzoylchloride and 4 g. of solid sodium carbonatewas added, the dry ice bath was removed, and the mixture was stirred for60 min. The inorganic solids were removed by filtration, washed withmethanol, and the combined organic phases evaporated to dryness. Thecrude product was dissolved in 100 ml. of dichloromethane, washed (l X1N sodium carbonate, 1 X water), dried (sodium sulfate) and evaporated.The crude product (1.7 g.) was separated by preparative layerchromatography to give 0.235 g. 17.5%) of l-benzoyl-3(R)-vinyl-4(S)-piperidineacetaldehyde as a colorless oil.

EXAMPLE 24 Preparation of rac. trans piperidineacetic acid methyl esterTo the solution of 0.476 g. of rac. trans l-benzoyl-3-vinyl-4-piperidineacetic acid in 4 ml. of methanol was added 9 ml. ofdiazomethane solution in ether (concentration ca. 3 g./130 ml.). Afterfew minutes an additional 9 ml. of diazomethane solution was added, andthen stirred at room temperature for 1 hour. The excess of diazomethanewas destroyed by addition of several drops glacial acetic acid, and thusresulted mixture was evaporated to dryness in vacuo, leaving 0.5 g. ofoily residue. The crude product was chromatographed on 7 Brinkman silicagel preparative plates with benzeneether 1:1 mixture. Elution with 95%ethanol gave 0.201

1-benzoyl-3-viny1-4- g. of oily rac. trans l-benzoyl-3-vinyl-4-piperidineacetic acid methyl ester.

EXAMPLE 25 Preparation of 1-benzoyl-3(S)-vinyl-4(S)- piperidineaceticacid methyl ester To a cooled solution containing 2.34 g. of l-benzoyl--3(S)-vinyl-4(S)-piperidineacetic acid in 20 ml. of methanol was added20 ml. of diazomethane solution in ether (concentration ca 3 g./130ml.). After few minutes an additional 20 ml. of diazomethane solutionwas added and then stirred at room temperature for minutes. The excessof diazomethane was destroyed by addition of several drops of glacialacetic acid, and thus resulted mixture was evaporated to dryness invacuo, leaving 2.9 g. of oil residue. The crude product waschromatographed on 26 Brinkman silica gel preparative plates withbenzene-ether 1:1 mixture. Elution with 95% ethanol gave 1.059 g. ofoily1-benzoyl-3(S)-vinyl- 4(S)-piperidineacetic acid methyl ester, [01],,l.6l (c 1.1193, CHCl EXAMPLE 26 Preparation of racemic3-(a-benzyloxycarbonylcyanomethyl) glutaric acid diethyl ester To theboiling solution of 37.24 g. of glutaconic acid diethyl ester and 70.08g. of benzylcyanoacetate in 100 ml. of anhydrous tetrahydrofuran wasadded dropwise 22.4 g. (0.20 mole) of potassium t-butoxide in 300 ml. ofanhydrous tetrahydrofuran over a hour-hour period. The reaction mixturewas stirred and refluxed for 12 hours. The solvent was removed bydistillation in vacuo. To the residue was added 100 ml. of water andextracted with 3 l. of benzene. The benzene extract was washed fourtimes with 100 ml. of water, dried over anhydrous sodium sulfate andevaporated in vacuo. The crude product was fractionally distilled togive 42.55 g. of racemic 3-(a-benzyloxycarbonylcyanomethyl)glutaric aciddiethyl ester, b.p. 167-174 at 0.15 mml-lg. Large scale runs average to61% yield.

EXAMPLE 27 Preparation of racemic 3-(l-benzyloxycarbonyl-lcyanopropyl)glutaric acid diethyl ester The mixture of 18 g. of racemic3-(abenzyloxycarbonylcyanomethyl)glutaric acid diethyl ester, 15.6 g. ofethyliodide and 6.72 g. of potassium t-butoxide in 200 m1. of anhydroustetrahydrofuran was stirred and refluxed for 3 hours, which it becameneutral. The precipitate formed during the reaction was separated byfiltration and washed with tetrahydrofuran. The combined filtrates wereevaporated to dryness, and after addition of 20 ml. of water, extractedwith l l. of benzene. The'benzene extract was washed with water, driedover anhydrous sodium sulfate and evaporated to dryness. The crudeproduct was fractionally distilled to give 11.35 g. of racemic 3-(1-benzyloxycarbonyl- 1 -cyanopropy1)glutaric acid diethyl ester, b.p.154-l59 at 25 microns. Large scale runs average to yield.

EXAMPLE 28 Preparation of racemic 3-(1-cyanopropyl)glutaric acid diethylester To the solution of 23.4 g. (0.06 mole) of 3-(1-benzyloxycarbonyl-1-cyanopropyl)glutaric acid diethyl ester in 600 ml.of ethanol was added 3 g. of 10% palladium on carbon, and hydrogenatedat room temperature and atmospheric pressure. After uptake of 0.06 moleof hydrogen, the reaction ceased. Catalyst was removed by filtrationthrough celite, and the filtrate was evaporated to dryness. The residue,2032 g., was heated at l70l80 in vacuo for 1 hour. After cooling to roomtemperature, it was dissolved in 1 l. of ether. The ethereal solutionwas washed three times with 50 ml. of concentrated aqeous solution ofsodium bicarbonate, and water, dried over anhydrous magnesium sulfateand evaporated to dryness to give 14.17 g. of racemic3-(l-cyanopropyl)glutaric acid diethyl ester, b.p. 8486 at 20 microns.

EXAMPLE 29 Preparation of racemic cis 4-ethoxycarbonylmethyl-5-ethyl-2-piperidone and racemic trans 4-ethoxycarbonylmethyl-Sethyl-2-piperidone To a solution of 101.23 g.(0.395 mole) of 3-(1- cyanopropyl) glutaric acid diethyl ester in 1200ml. of absolute ethanol was added 31.8 g. of Raney nickel, andhydrogenated at 1 10 atm and temperature, which in the course of 3 hoursrose slowly from room to 152C. After cooling to room temperature, thecatalyst was separated by filtration through celite and the filtrateevaporated to dryness in vacuo. On trituration with ether, 57.6 g. ofracemic trans ethoxycarbonylmethyl-SethyLZ-piperidone,

8688 was obtained. After one recrystallization from.

methylene chloride-ether, m.p. was 89-9l.

The mother liquors were evaporated to give 23.5 g.

of oily residue, which was chromatographed on a 2 kg. silica gel column.The elution with ethanol-chloroform mixture gave 16 g. of racemic cis 4-ethoxycarbonylmethyl-Sethyl-2-piperidone.

' EXAMPLE 30 of racemic trans 4 temperature, then diluted with 50 ml. ofwater and extracted with 1 l. of methylene chloride. Methylene chlorideextract was washed with water (3 X 50 m1.), dried over anhydrous sodiumsulfate and evaporated to dryness. The residue was dissolved in 7 ml. ofice-cold 1N hydrochloric acid, the resulting solution diluted with 100ml. of water and washed 5 times by shaking with 50 ml. of ether. It wasthen made alkaline with 8 ml. of 1N sodium hydroxide and extracted with1 1. of methylene chloride. Methylene chloride extract was washed threetimes with 50 ml. of water, dried over an-. hydrous sodium sulfate andevaporated to dryness, to give 0.591 g. (99%) of racemic trans3-ethyl-4- piperidineacetic acid ethyl ester b.p. 91-92 (bath) at 0.5mmHg.

EXAMPLE 31 Preparation of racemic cis 6-methoxy-4-{3-[ l-benzoyl-3-vinyl-4-piperidyll-2-oxopropyl }quinoline from 6- methoxylepidine andracemic N-benzoylmeroquinene methyl ester [cislbenzoyl-3-vinyl-4-piperidineacetic acid methyl ester] To a solutioncontaining about 0.032 mole of lithium diisopropyl amide [prepared at 20in an atmosphere of dry nitrogent by the addition of 6 ml. of drydiisopropylamine to 15.5 ml. of phenyllithium in benzene-ether (7:3)]were added dropwise a solution containing 5.6 g. of 6-methoxylepidine in60 ml. of anhydrous tetrahydrofuran. The reaction mixture was stirredfor 20 minutes. To the practically homogeneous, dark-brown solution of6-methoxylepidyl lithium thus obtained was added dropwise over a periodof 20 minutes a solution containing 4.6 g. of racemicN-benzoylmeroquinene methyl ester in 60 ml. of anhydroustetrahydrofuran. After the addition was completed, stirring wascontinued for 60 minutes. During the whole operation the reactiontemperature was maintained at 20. Thereafter, ice and water were addedand the reaction mixture was neutralized to a pH 8 with acetic acid and10% sodium bicarbonate. The aqueous phase was extracted thoroughly withether. The ethereal extract was washed with water, dried over anhydrousmagnesium sulfate and evaporated. The residue was adsorbed on a 550 g.neutral alumina column (activity ll). After elution of unreacted6-methoxylepidine with benzene, the amorphous racemic cis6-methoxy-4-{3-[ l-benzoyl-3-vinyl- 4-piperidyl]-2-oxopropyl }quinolinewas eluted with benzene containing 20-50% of ethyl acetate.

EXAMPLE 32 Preparation of 6-'methoxy-4{3-[l-benzoyl-3(R)-vinyl-4(S)-piperidyl]-2-oxopropyl quinoline from 6 methoxy-lepidine andN-benzoyl meroquinene ethyl ester 1 To a solution of ca. 0.07 mole oflithium diisopropyl amide [prepared by addition of ml. of drydiisopropyl amine in 10 ml. of toluene to 35 ml. of ca. 2 molar n-butyllithium in hexane, at -78 under nitrogen] was added dropwise 10 min.)with stirring a solution of 13 g. (0.075 mole) of -methoxy-lepidine in120 m1. of tetrahydrofuran. The mixture was stirred at 78 for 30 min.,and there was added dropwise (10 min.) a solution of 10.5 g. (0.0345mole) of N- benzoylmeroquinene ethyl ester in 150 m1. oftetrahydrofuran. Stirring was continued at 78 for 30 min. The coolingbath was removed and the stirring was continued for another 30 min.Water was added, the aqueous layer was neutralized (pl-l ca. 8) withacetic acid and extracted thoroughly with ether. The ethereal phase waswashed (water), dried (magnesium sulfate) and evaporated in vacuo. Theresidue was absorbed on 600 g. of neutral alumina, activity 11; afterelution of excess 6-methoxy-lepidine with benzene, elution withbenzene-ethyl acetate (1:1) afforded amorphous 6- methoxy-4 {3-[l-benzoyl-3(R)-vinyl-4(S)-piperidy1]-2- oxopropyl}-quinoline; [01] 27.3(c 1.205; chloroform).

EXAMPLE 33 Preparation of 6-methoxy-4 {-3-[ l-benzoyl-3(R)-vinyl-4(S)-piperidyl]-2-oxopropyl quinoline from 6- methoxylepidine andN-benzoyl-meroquinene methyl ester A condensation reaction carried outin analogous way as in Example 30a with 1.8 g. (0.0104 mole) of 6-methoxylepidine and 1.49 g. (0.0052 mole) of N- benzoyl-meroquinenemethyl ester (phenyl lithium was used instead of n-butyl lithium)yielded after a similar technique and separation by columnchromatography 6-methoxy-4{3-[1-benzoy1-3(R)-vinyl-4(S)-piperidyl]-2-oxopropyl}-quinoline.

EXAMPLE 34 Preparation of 7-chloro-4-{3-[l-benzoyl-3(R)-vinyl-4(S)-piperidyl]-2-oxopropyl quinoline from 7- chlorolepidine andN-benzoyl-meroquinene ethyl ester To a dry ice cooled solution of ca.0.061 mole of lithium diisopropyl amide [prepared in an atmosphere ofdry nitrogen by addition of 10 ml. (ca. 0.07 mole) of diisopropylaminein 30 ml. of tetrahydrofuran to 30 ml. of ca. 2M n-butyllithium inhexane] was added dropwise (20 min.) a solution of 11 g. (0.061 mole) of7- chlorolepidine in ml. of tetrahydrofuran. The resulting brownsuspension was stirred at 78 for 30 min., then there was added asolution of 9.2 g. (0.0305 mole) of N-benzoyl-meroquinene ethyl ester in60 ml. of tetrahydrofuran. Stirring was continued at 78 for 40 min.After removing the cooling bath, stirring was continued for another 40min. After addition of 50 ml. of water, the mixture was neutralized withacetic acid and the pH was adjusted to ca. 8 by addition of 10% sodiumbicarbonate. The aqueous phase was extracted thoroughly with ether, theethereal phases were washed (2 X 10% sodium bicarbonate), dried(magnesium sulfate) and evaporated to dryness. Crystallization fromacetone-ether afforded crystalline 7-chloro-4-{3-[1-benzoyl-3(R)-viny1-4(S)-piperidyl]-2- oxopropyl}quinoline; the motherliquor was absorbed on 300 g. of neutral alumina, activity 11, andelution with ethyl acetate afforded additional amounts of 7-chloro-4-{3-[1-benzoyl-3(R)-vinyl-4(S)-piperidyl]-2-oxopropyl}quinoline; m.p. l47-l48 (acetone); [(11 38.7 (c 1.00,chloroform).

EXAMPLE 35 Preparation of epimeric 7-chloro-4-{3-[3(R)-vinyl- 4(S)-piperidy1]-2-hydroxypropyl }-quinolines from 7-ch1oro-4-{3-[1-benzoyl-3(R)-vinyl-4(S)-piperidyl]-2- oxopropyl}quinolineTo an ice cold solution of 7.84 g. (0.018 mole) of 7-chloro-4-{3-[1-benzoyl-3(R)-vinyl-4(S)-piperidyl]-2- oxopropyl}quinolinein 200 ml. of methanol was added excess solid sodium borohydride, andthe solution was stirred for 60 min. at 0. Fifty ml. of water was added,

1. A COMPOUND FOR THE FORMULA
 2. A compound in accordance with claim 1,wherein R2 is vinyl; R3 is hydrogen and R4 is benzoyl, i.e.,1-benzoyl-3(S)-vinyl-4(S)-piperidineacetic acid or its racemate.
 3. Acompound in accordance with claim 1, wherein R2 is vinyl; R3 is ethyland R4 is benzoyl, i.e., racemic trans1-benzoyl-3-vinyl-4-piperidineacetic acid ethyl ester.
 4. A compound inaccordance with claim 1, wherein R2 is vinyl; R3 is methyl and R4 isbenzoyl, i.e., 1-benzoyl-3(S)-vinyl-4(S)-piperidineacetic acid methylester or its racemate.
 5. A compound in accordance with claim 1, whereinR2 is ethyl; R3 is ethyl, and R4 is hydrogen, i.e., racemic trans3-ethyl-4-piperidineacetic acid ethyl ester.
 6. A racemic compound ofthe formula
 7. A compound in accordance with claim 6, wherein R3 ishydrogen and R4 is benzoyl, i.e., racemic cis1-benzoyl-3-vinyl-4-piperidineacetic acid.
 8. A compound in accordancewith claim 6, wherein R3 is methyl and R4 is benzoyl, i.e., racemic cis1-benzoyl-3-vinyl-4-piperidineacetic acid methyl ester.
 9. A compound inaccordance with claim 6, wherein R3 is ethyl and R4 is benzoyl, i.e.,racemic cis 1-benzoyl-3-vinyl-4-piperidineacetic acid ethyl ester.